CGAS in systemic lupus erythematosus (SLE)

ABSTRACT

The present invention provides therapeutic strategies for treatment of severe debilitating diseases associated with IFN-I due to cGAS activation. In one aspect, the invention provides compounds of Formula (I): [Formula should be inserted here] and pharmaceutical uses thereof. In another aspect, the invention provides methods for treating an autoimmune disease or a monogenic disorder by administering an effective amount of a compound of Formula (I).

This application is a U.S. national phase of International ApplicationNo. PCT/US2016/029396, filed on Apr. 26, 2016, which claims priority toU.S. Provisional Application No. 62/155,389 filed Apr. 30, 2015, both ofwhich are incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

The innate immune system senses the presence of microbes or damage viagermline-encoded receptors, which detect pathogen associated molecularpatterns (PAMPs) or damage-associated molecular patterns (DAMPs).Nucleic acids constitute a major molecular pattern that is recognizedduring infection by viruses or intracellular bacteria and that resultsin the stimulation of type I interferons (IFN-I) and other cytokines.However, chronic or inappropriate activation of nucleic acid-sensingpathways are also implicated in inflammatory and autoimmune diseases.

Evidence for the involvement of type I IFNs (IFN-I) in the pathogenesisof systemic autoimmune disorders such as systemic lupus erythematosus(SLE) (Elkon, K. B. and A. Wiedeman, Type I IFN system in thedevelopment and manifestations of SLE. Curr Opin Rheumatol, 2012. 24(5):p. 499-505) as well as in rare monogenic disorders includingAicardi-Goutierre's Syndrome (AGS) and spondyloenchondrodysplasia(SPENCD), is demonstrated by the increased expression of IFN-Istimulated genes (ISGs) in peripheral blood cells. SLE is aheterogeneous and flaring disease which can cause diseases of the skin,heart, lung, kidney, joints, nervous system etc., which make it verydifficult to treat. AGS is a rare inherited ‘orphan’ disease thataffects children. It is characterized predominantly by abnormalities inthe skin and brain resulting in severe brain defects and even death insome of these children (˜35% of patients die by age 15). This disease isalso associated with the expression of IFN-I and some of these patientsdevelop features similar to SLE. In a reciprocal fashion, 1-2% of SLEpatients have mutations in TREX1. The association of TREX1 mutationswith SLE remains the strongest single association of a gene identifiedso far (highest odds ratio). There is currently no effective treatmentfor the severe, debilitating disorder of AGS.

How, where and when IFN-I is initially stimulated, and which of theapproximately 20 IFN-I subtypes are expressed in each disease, has beendifficult to determine. In vitro studies (Santer, D. M., et al., Potentinduction of IFN-alpha and chemokines by autoantibodies in thecerebrospinal fluid of patients with neuropsychiatric lupus. J Immunol,2009. 182(2): p. 1192-201), have revealed that IFN-alpha (IFNa) isinduced by SLE immune complexes (IC) containing (ribo)nucleoproteinantigens (Lovgren, T., et al., Induction of interferon-alpha by immunecomplexes or liposomes containing systemic lupus erythematosusautoantigen-and Sjogren's syndrome autoantigen-associated RNA. ArthritisRheum, 2006. 54(6): p. 1917-27). However, the in vitro studies do notaddress how IFN-I may be induced prior to the formation of IC. CytosolicDNA induces type I interferons and other cytokines which are importantfor antimicrobial defense but can also trigger autoimmunity. Experimentsdemonstrating that the serum from a significant proportion of SLE familymembers without autoantibodies induce ISGs in responder cells (Niewold,T. B., et al., High serum IFN-alpha activity is a heritable risk factorfor systemic lupus erythematosus. Genes Immun, 2007. 8(6): p. 492-502)as well as incomplete neutralization of ISGs in clinical trials usingbiologics targeting IFN-α, suggest that other IFN-I may well be involvedin SLE (Petri, M., et al., Sifalimumab, a human anti-interfron-alphamonoclonal antibody in systemic lupus erythematosus: a phase Irandomized, controlled, dose-escalation study. Arthritis Rheum, 2013.65(4): p. 1011-21). Moreover, in a mouse model of AGS caused bydeficient expression of the 3-5′ DNA exonuclease, TREX1, accumulation ofintracellular DNA is responsible for cell intrinsic production of IFNb.

While many DNA sensors have been described, the recent discovery ofcyclic GAMP synthase, (cGAS) (Wu. J., et al., Cyclic GMP-AMP is anendogenous second messenger in innate immune signaling by cytosolic DNA.Science, 2013. 339(6121): p. 826-30) (Sun, L., et al., Cyclic GMP-AMPsynthase is a cytosolic DNA sensor that activates the type I interferonpathway. Science, 2013. 339(6121): p. 786-91), is of particular interestas it has been shown to play a pivotal role in virus-induced as well asDNA damage-induced IFN-I production. Following binding of doublestranded (ds)-DNA to a positively charged pocket of cGAS, the enzymeundergoes a conformational change revealing a catalytic cleft whichresults in the synthesis of the cyclic dinucleotide, cyclic GMP-AMP(cGAMP) (Diner, E. J., et al., The Innate Immune DNA Sensor cGASProduces a Noncanonical Cyclic Dinucleotide that Activates Human SLING.Cell Rep, 2013. 3(5): p. 1355-61). cGAMP binds to the adapter protein,STING, which triggers activation of TBK, phosphorylation of IRF3 withresulting transcription of IFN-b (Sun, 2013) (Wu, 2013). In cells thatare deficient in TREX1, it has recently been shown that DNA triggersIFN-b selectively through the cGAS pathway (Gao, D., et al. Activationof cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. ProcNatl Acad Sci USA 112, E5699-5705 (2015), 26371324); Gray, E. E.,Treuting, P. M., Woodward, J. J., and Stetson. D. B. 2015. Cutting Edge:cGAS Is Required for Lethal Autoimmune Disease in the Trex1-DeficientMouse Model of Aicardi-Goutieres Syndrome. J Immunol 195:1939-1943).

There remains a need in the art for treatment of severe debilitatingdiseases associated with IFN-I due to cGAS activation. Understanding themechanism how cGAS/cGAMP contribute to IFN-I stimulation in SLE patientsallows for directed therapeutic approaches which we are pursuing in SLEand possibly other autoimmune diseases associated with cytosolic DNA asa Danger Associated Molecular Pattern (DAMP).

SUMMARY OF THE INVENTION

Systemic Lupus Erythematosus (SLE) is strongly associated with increasedexpression of type I interferon (IFN-I) (Elkon, 2012). Both genetic aswell as experimental studies indicate that IFN-I plays a central role inthis disease (Lovgren, 2006) (Niewold. 2007). IFN-I can be stimulated byseveral pathways including cGAS (Cyclic di-GMP-AMP Synthase), a recentlydiscovered cytosolic DNA sensor (Wu, 2013; Sun, 2013). cGAS is activatedby ds-DNA, catalyzes the production of novel second messenger, cGAMPthat potently activates type 1 IFN through STING and IRF3 pathway. Thediscovery of cGAS means that any microbe with DNA that stimulates geneexpression by the transcription factors NF-κB and IRF3 should alsosignal via a cyclic dinucleotide made by the host cell via cGAS. Thepathway is also likely to be important for the sensing of self DNA,which can lead to autoimmunity. Since cGAS has catalytic activity, it ispossible that a small-molecule inhibitor could have therapeuticpotential for autoimmune diseases.

In view of the key role that cGAS plays in DNA stimulated IFN-bproduction and the suspected role of this pathway in diseases associatedwith high expression of ISGs, in silico screening of chemical and druglibraries was performed in order to identify candidate drugs predictedto block cGAS activity. Several candidates were identified bycomputational analysis, including hydroxychloroquine (HCQ) andquinacrine (QC), belonging to the antimalarial class of drugs, that werepredicted to interact with cGAS and ds-DNA. Studies validated thatseveral antimalarial drugs were effective inhibitors of IFN-b productionand that they functioned by inhibiting dsDNA stimulated cGAS productionof cGAMP.

In an effort to identify drugs to block cGAS activity, we performed insilico screening of chemical and drug libraries and identified severalcommonly used antimalarial drugs for the treatment of SLE, predicted tointeract strongly with cGAS by computational analysis (FIG. 1). We haveverified experimentally that these antimalarial drugs block DNA bindingto cGAS (FIG. 1). Antimalarial drugs including HCQ could inhibit thecGAS activity and cGAMP production in vitro (FIG. 2). More importantly,they could inhibit the type I IFN production when cells were transfectedwith dsDNA. Our results provide a novel mechanism of action ofantimalarial drugs that are used in the treatment of Lupus and RA andother autoimmune disorders.

It has been reported that the antimalarial drugs hydroxychloroquine andquinacrine induce remissions of SLE and rheumatoid arthritis. However,despite the use of hydroxychloroquine and quinacrine as therapeuticdrugs for autoimmune disease, their mechanism of action still remainsunclear and controversial. Current therapy for SLE such ascorticosteroids, cyclophosphamide and hydroxychloroquine were introducedseveral decades ago and, although used, were not approved by FDA forSLE. Benlysta (HGS/GSK) anti-BLys monoclonal antibody (mAb) is the firstand only approved SLE therapy in 50 years. Although clinical outcomefollowing Benlysta treatment was better than placebo, the difference wassmall. So there is still a large unmet medical need for therapeutictarget identification and new drug development for effective SLEtreatment. The present invention provides therapeutic strategies fortreatment of severe debilitating diseases associated with IFN-I due tocGAS activation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an electrophoretic mobility shift assay (EMSA) showing thatHCQ blocks dsDNA/cGAS binding.

FIG. 2 is (A) A representative TLC analysis of Quinacrine inhibition ofcGAS turnover; (B) Quantification of cGAS inhibition by HCQ derivatives;(C) summary of the 95% confidence intervals for the IC₅₀ of eachassociated inhibitor; and (D) binding affinity correlated with −log(IC₅₀).

FIG. 3 shows (A) the inhibition of the IFNb induction with antimalarialdrugs; and (B and C) the different capability of antimalarial drugs toinhibit IFNb production as shown by inhibition curves and IC₅₀.

FIG. 4 shows the binding of 32P-c-di-AMP (2 nM) by STING (170 μM)monitored in the presence of unlabeled c-di-AMP (200 μM) and HCQ withdifferent concentrations.

FIG. 5 is (A) QPCR analysis of cGAS expression from healthy controls(CNT, n=20) and SLE (n=51); (B) cGAS expression correlated with IFNscore in SLE patients; and (C) Western blot assay for the phosphorylatedIRF3 expression.

FIG. 6 shows (A) the abundance of cGAMP THP1 cells were transfected withHT-DNA quantized by mass spectrometry using SRM; and (B) the PBMC forcGAMP expression by LC/MS/MS in SLE and RA patients.

FIG. 7 shows cGAS activity of compounds X5, X6 and X7 by in vitrobiochemical assay.

FIG. 8 shows the effect of compound X6 on spleen mass in TREX1 KO mouse.

FIG. 9 shows the effect of compound X6 on the expression of ISG15 andCXCL10 in TREX1 KO mouse heart.

FIG. 10 shows the effect of compound X6 on the expression of ISG15 andISG20 in TREX1 KO mouse spleen.

FIG. 11 shows the effect of compound X6 on the expression of IFNb inTREX1 KO mouse heart.

FIG. 12 shows the effect of compound X6 on Trex1−/− KO mouse cGAMPexpression compared to SPLENDA™ treatment.

FIG. 13 shows the Trex1−/− Heart Pathology total score for compound X6.

FIG. 14 shows the effect of compound X6 on Trex1−/− heart endocardialinflammation.

FIG. 15 shows the effect of compound X6 on Trex1−/− heart endocardialfibrosis.

FIG. 16 shows the effect of compound X6 on Trex1−/− Heart endocardialinflammation/fibrosis.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides therapeutic strategies for treatment ofsevere debilitating diseases associated with IFN-I due to cGASactivation.

Before the present invention is described, it is to be understood thatthis invention is not limited to particular embodiments described, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present invention will be limited only by the appended claims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are now described. All publications mentioned herein areincorporated herein by reference to disclose and describe the methodsand/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “acompound” includes a plurality of such compounds, and reference to “themethod” includes reference to one or more methods, method steps, andequivalents thereof known to those skilled in the art, and so forth.

In the broadest sense, as used herein, the term “autoimmune disease,”refers to a disease wherein a patient's immune system is producing anunwanted immune response to one or more of their own proteins.Representative examples of autoimmune diseases include systemic lupuserythematosus (SLE), lupus nephritis (LN), rheumatoid arthritis,juvenile rheumatoid arthritis, Wegener's disease, inflammatory boweldisease, idiopathic thrombocytopenic purpura (ITP), thromboticthrombocytopenic purpura (TTP), autoimmune thrombocytopenia, multiplesclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myastheniagravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen'ssyndrome, scleroderma, polymyositis and glomerulonephritis. Preferably,the autoimmune disease is SLE.

In the broadest sense, as used herein, the term “monogenic disorder,”refers to a disease that is the result of a single defective gene on theautosomes. Representative monogenic disorders include rare monogenicdisorders, Aicardi-Goutierre's Syndrome (AGS) andspondyloenchondrodysplasia (SPENCD). Preferably, the monogenic disorderis AGS.

A “biological sample” encompasses a variety of sample types obtainedfrom an individual and can be used in a diagnostic or monitoring assay.The definition encompasses blood and other liquid samples of biologicalorigin, solid tissue samples such as a biopsy specimen or tissuecultures or cells derived there from and the progeny thereof. Thedefinition also includes samples that have been manipulated in any wayafter their procurement, such as by treatment with reagents,solubilization, or enrichment for certain components, such aspolynucleotides. The term “biological sample” encompasses a clinicalsample, and also includes cells in culture, cell supernatants, celllysates, serum, plasma, biological fluid, and tissue samples.

As used herein, the terms “treatment”, “treating”, and the like, referto obtaining a desired pharmacologic and/or physiologic effect. Theeffect may be prophylactic in terms of completely or partiallypreventing a disease or symptom thereof and/or may be therapeutic interms of a partial or complete cure for a disease and/or adverse effectattributable to the disease. “Treatment”, as used herein, covers anytreatment of a disease in a mammal. particularly in a human, andincludes: (a) preventing the disease from occurring in a subject whichmay be predisposed to the disease but has not yet been diagnosed ashaving it: (b) inhibiting the disease, i.e., arresting its development;and (c) relieving the disease, i.e., causing regression of the disease.

The terms “individual,” “subject,” and “patient,” used interchangeablyherein, refer to a mammal, including, but not limited to, murines,simians, humans, mammalian farm animals, mammalian sport animals, andmammalian pets. Preferably, the subject herein is human.

The present invention relates to compounds of Formula (I) or a prodrugor metabolite thereof,

wherein

-   -   R₁ is —OH, —NH₂, —N(H)C(O)R₇ or —NO₂;    -   R₂ is —H or —OCH₃;    -   R₃ and R₄ are independently —H or —CH₃;    -   R₅ and R₆ are independently —H, —CH₃, —CH₂CH₂SH,

-   -   R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —CH₃,        —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,        —CH₂CH₂CH₂CH₂CH₂CH₃, —CF₃, —CH₂CF₃ or

-   -    and    -   n is 2 or 3.

In some embodiments,

-   -   R₁ is —NH₂.

In some embodiments, R₇ is —NH₂ or —N(H)C(O)R₇;

-   -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is,

-   -   R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —CH₃,        —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,        —CH₂CH₂CH₂CH₂CH₂CH₃, —CF₃, —CH₂CF₃ or

-   -    and    -   n is 2.

In some embodiments,

-   -   R₁ is —NH₂ or —N(H)C(O)R₇;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is,

-   -   R₇ is —OCH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CF₃ or

-   -    and    -   n is 2; and

In some embodiments,

-   -   R₁ is —NH₂;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -    and    -   n is 2.

In some embodiments,

-   -   R₁ is —NH₂;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -   and n is 2.

In some embodiments,

-   -   R₁ is —NH₂;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -    and    -   n is 2.

In some embodiments, R₁ is N(H)C(O)R₇.

In some embodiments,

-   -   R₁ is —N(H)C(O)R₇;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -    and    -   n is 2.

In some embodiments,

-   -   R₁ is —N(H)C(O)CH₂CH₂CH₂CH₂CH₃;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -    and    -   n is 2.

In some embodiments,

-   -   R₁ is —N(H)C(O)CF₃;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -    and    -   n is 2.

In some embodiments,

-   -   R₁ is —N(H)C(O)R₇;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -   R₇ is

-   -    and    -   n is 2.

The present invention also relates to compounds of Formula (III) or aprodrug or metabolite thereof,

wherein R₁ is —Cl, —OH, —NH₂, or —NO₂; R₆ is

and n is 3 or 4.

In some aspects, R₁ is —Cl; R₆ is

and n is 3.

In other aspects, R₁ is —Cl; R₆ is

and n is 4.

In other aspects, R₁ is —Cl; R₆ is

and n is 3.

In some aspects, R₁ is —Cl; R₆ is

and n is 4.

In some aspects, R₁ is —Cl; R₆ is

and n is 3.

In other aspects, R₁ is —Cl; R₆ is

and n is 4.

In some aspects, R₁ is OH; R₆ is

and n is 3.

In some aspects, R₁ is OH; R₆ is

and n is 4.

In some aspects, R₁ is OH; R₆ is

and n is 3.

In other aspects, R₁ is OH; R₆ is

and n is 4.

In other aspects, R₁ is OH; R₆ is

and n is 3.

In other aspects, R₁ is OH; R₆ is

and n is 4.

In some aspects, R₁ is NH₂; R₆ is

and n is 3.

In some aspects, R₁ is NH₂; R₂ is

and n is 4.

In other aspects, R₁ is NH₂; R₂ is

and n is 3.

In other aspects, R₁ is NH₂; R₆ is

and n is 4.

In some aspects, R₁ is NH₂; R₆ is

and n is 3.

In some aspects, R₁ is NH₂; R₆ is

and n is 4.

In some aspects, R₁ is NO₂; R₆ is

and n is 3.

In some aspects, R₁ is NO₂; R₆ is

and n is 4.

In some aspects, R₁ is NO₂; R₆ is

and n is 3.

In other aspects, R₁ is NO₂; R₆ is

and n is 4.

In other aspects, R₁ is NO₂; R₆ is

and n is 3.

In other aspects, R₁ is NO₂; R₆ is

and n is 4.

Other aspects of the present invention relate to compounds of Formula(II) or a prodrug or metabolite thereof,

wherein R₁ is H, Cl, OH, NH₂ or NO₂; R₂ is H or —OCH₃; R₃ and R₄ areindependently H or CH₃; R₅ and R₆ are independently H, CH₃, —CH₂CH₂SH,

and n is 2 or 3.

In a preferred aspect, R₁ is NH₂; R₂ is —OCH₃; R₃ is CH₃; R₄ is H; R₅ isCH₃; R₆ is

and n is 2.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ and R₆ are H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ and R₆ are CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ and R₆ are —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is H, R₆ is CH₃, and n is 2.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R and R₄ are H,R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, R₂ is H, R₃ and R₄ are H, R₅ is

R₆ is —CH₂CH₂SH, and n is 2.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ are H,R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ and R₆ are H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ and R₆ are CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ and R₆ are —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ and R₆ are H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ and R₆ are CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ and R₆ are —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is H, R₄ isCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ and R₆ are H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ and R₆ are CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ and R₆ are —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is H and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is H, R₃ is CH₃, R₄ isH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ and R₆ are H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ and R₆ are CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ and R₆ are —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areH, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ and R₆ are H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ and R₆ are CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ and R₆ are —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, R₂ is —OCH₃, R₃ and R₄ are CH₃, R₅ is CH₃, R₆is

and n is 2.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ and R₄ areCH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ and R₆ are H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ and R₆ are CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ and R₆ are —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄ isCH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is CH₃, SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is —CH₂CH₂SH and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is H, R₄is CH₃, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ and R₆ are H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ and R₆ are CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ and R₆ are —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ and R₆ are

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is H, R₆ is

n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is H and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is CH₃, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is —CH₂CH₂SH, R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is H, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is H, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is —CH₂CH₂SH, R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is CH₃, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is H, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is CH₃, R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is —CH₂CH₂SH, and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is H, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is CH₃, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is —CH₂CH₂SH, R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

In some aspects, R₁ is H, Cl, OH, NH₂ or NO₂, R₂ is —OCH₃, R₃ is CH₃, R₄is H, R₅ is

R₆ is

and n is 2 or 3.

The invention also provides pharmaceutical compositions of the compoundsdisclosed herein. In some embodiments, the pharmaceutical compositionmay include a compound of formulae (I) or (II) and a pharmaceuticallyacceptable carrier, diluent or excipient.

The invention further relates to the treatment of autoimmune diseases bythe administration of a compound of a compound of Formula (I) or acompound of Formula (II). Compounds of Formula (I) and Formula (II) canbe useful for the treatment of autoimmune diseases including systemiclupus erythematosus (SLE), lupus nephritis (LN), rheumatoid arthritis,juvenile rheumatoid arthritis, Wegener's disease, inflammatory boweldisease, idiopathic thrombocytopenic purpura (ITP), thromboticthrombocytopenic purpura (TTP). autoimmune thrombocytopenia, multiplesclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, myastheniagravis, vasculitis, diabetes mellitus, Reynaud's syndrome, Sjorgen'ssyndrome, scleroderma, polymyositis and glomerulonephritis. Preferably,the autoimmune disease is SLE.

The invention further relates to the treatment of monogenic disorders bythe administration of a compound of Formula (I) or a compound of Formula(II). Compounds of Formula (I) and Formula (II) can be useful for thetreatment of monogenic disorders including Aicardi-Goutierre's Syndrome(AGS) or spondyloenchondrodysplasia (SPENCD). Preferably, the monogenicdisorder is AGS.

In one embodiment, the method of treatment includes the administrationof a pharmaceutical described herein.

The invention also relates to a method for the treatment of anautoimmune disease or a monogenic disorder, the method comprisingadministering an effective amount of a compound of Formula (III) or aprodrug or metabolite thereof,

wherein

-   -   R₁ is —H, halogen, —OH, —OCH₃, —NH₂, —NMe₂, —N(H)C(O)R₇ or —NO₂,        -   wherein R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃,            —CH₃, —CH₂CH₃, —CH₂ CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,            —CH₂CH₂CH₂CH₂CH₂CH₃, —CF₃, —CH₂CF₃ or

-   -   ring X is absent or

-   -    wherein R₂ is —H, halogen, —NMe₂, —OCH₃ or —OCH₂CH₃;    -   X is —H, —NH₂,

-   -    wherein    -   R₃ is —H or —CH₃;    -   R₄ is —H or —CH₃;    -   R₅ and R₆ are independently —H, —CH₃, —CH₂CH₃, —CH₂CH₂SH,        —CH₂CH₂OH,

-   -   R_(Y) is —NO₂, —C(O)OCH₂CH₃ or —N(H)SO₂Me; and    -   n is 2 or 3;        to a patient in need thereof.

In some embodiments of the method, the compound is of formula (IIIa):

wherein

-   -   R₁ is —H, halogen, —OH, —OCH₃, —NH₂, —N(H)C(O)R₇ or —NO₂,        -   wherein R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃,            —CH₃, —CH₂CH₃, —CH₂ CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,            —CH₂CH₂CH₂CH₂CH₃, —CF₃, —CH₂CF₃ or

-   -   X is

-   -    wherein    -   R₃ is —H or —CH₃;    -   R₄ is —H or —CH₃;    -   R₅ and R₆ are independently —H, —CH₃, —CH₂CH₃ or —CH₂CH₂OH; and    -   n is 2 or 3.

In some embodiments of the method, the compound is of formula (IIIb):

wherein

-   -   R₁ is —H, halogen, —OH, —OCH₃, —NH₂, —N(H)C(O)R₇ or —NO₂,        -   wherein R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃,            —CH₃, —CH₂CH₃, —CH₂ CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,            —CH₂CH₂CH₂CH₂CH₂CH₃, —CF₃, —CH₂CF₃ or

-   -   R₂ is —H, halogen, —OCH₃ or —OCH₂CH₃;    -   X is —NH₂,

-   -    wherein    -   R₃ is —H or —CH₃;    -   R₄ is —H or —CH₃;    -   R₅ and R₆ are independently —H, —CH₃, —CH₂CH₃, —CH₂CH₂SH,        —CH₂CH₂OH,

-   -   R_(Y) is —NO₂, —C(O)OCH₂CH₃ or —N(H)SO₂Me; and    -   n is 2 or 3.

In some embodiments of the method, X is —NH₂.

In some embodiments of the method, X is

In some embodiments of the method, X is

In some embodiments of the method, X is

In some embodiments of the method, the compound of Formula (IIIc) or aprodrug or metabolite thereof,

wherein

-   -   R₁ is —H, halogen, —OH, —OCH₃, —NH₂, —N(H)C(O)R₇ or —NO₂;    -   R₂ is —H or —OCH₃;    -   R₃ and R₄ are independently —H or —CH₃;    -   R₅ and R₆ are independently —H, —CH₃, —CH₂CH₃, —CH₂CH₂SH,        —CH₂CH₂OH,

-   -   R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —CH₃,        —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,        —CH₂CH₂CH₂CH₂CH₂CH₃, —CF₃, —CH₂CF₃ or

-   -    and    -   n is 2 or 3.

In some embodiments of the method,

-   -   R₁ is —H, —Cl, —OH, —NH₂, —N(H)C(O)R₇ or —NO₂;    -   R₂ is —H or —OCH₃;    -   R₃ and R₄ are independently —H or —CH₃;    -   R₅ and R₆ are independently —H, —CH₃, —CH₂CH₂SH,

-   -   R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —CH₃,        —CH₂CH₃, —CH₂ CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₂CH₃,        —CH₂CH₂CH₂CH₂CH₂CH₃, —CF₃, —CH₂CF₃ or

-   -    and    -   n is 2 or 3.

In some embodiments of the method,

-   -   R₁ is —NH₂ or —N(H)C(O)R₇;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -   R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —CH₃,        —CH₂CH₃, —CH₂ CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,        —CH₂CH₂CH₂CH₂CH₂CH₃, —CF₃, —CH₂CF₃ or

-   -    and    -   n is 2.

In some embodiments of the method,

-   -   R₁ is NH₂ or N(H)C(O)R₇;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -   R₇ is —OCH₂CH₃, CH₂CH₂CH₂CH₂CH₃, —CF₃ or

-   -    and    -   n is 2.

In some embodiments of the method,

-   -   R₁ is —NH₂;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -    and    -   n is 2.

In some embodiments of the method,

-   -   R₁ is —NH₂;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -    and    -   n is 2.

In some embodiments of the method,

-   -   R₁ is —NH₂;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -    and    -   n is 2.

In some embodiments of the method, R₁ is —N(H)C(O)R₇.

In some embodiments of the method, R₁ is —N(H)C(O)R₇;

-   -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -    and    -   n is 2.

In some embodiments of the method,

-   -   R₁ is —N(H)C(O)CH₂CH₂CH₂CH₂CH₃;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -    and    -   n is 2.

In some embodiments of the method,

-   -   R₁ is —N(H)C(O)CF₃;    -   R₂ is —OCH₃;    -   R₃ is —CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -    and    -   n is 2.

In some embodiments of the method,

-   -   R₁ is —N(H)C(O)R₇;    -   R₂ is —OCH₃; R₃ is CH₃;    -   R₄ is —H;    -   R₅ is —CH₃;    -   R₆ is

-   -   R₇ is

-   -    and    -   n is 2.

In some embodiments of the method, the treatment is of an autoimmunedisease. The autoimmune disease may be selected from the groupconsisting of systemic lupus erythematosus (SLE), lupus nephritis (LN),rheumatoid arthritis, juvenile rheumatoid arthritis, Wegener's disease,inflammatory bowel disease, idiopathic thrombocytopenic purpura (ITP),thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenia,multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies,myasthenia gravis, vasculitis, diabetes mellitus, Reynaud's syndrome,Sjorgen's syndrome, scleroderma, polymyositis and glomerulonephritis.

In some embodiments of the method, the autoimmune disease is SLE.

In some embodiments of the method, the autoimmune disease involvesinhibition of cGAS activity.

In some embodiments of the method, the treatment of a monogenicdisorder.

In some embodiments of the method, the monogenic disorder isAicardi-Goutierre's Syndrome (AGS) or spondyloenchondrodysplasia(SPENCD).

In some embodiments of the method, the monogenic disorder is AGS.

EXAMPLES Example 1

Anti-malarial Drugs are Predicted to Block cGAS-DNA Interaction byComputational Analysis

The structural domains of cGAS present two highly attractive drugtargets, the catalytic site and a regulatory site, both with establishedkey residues in relatively compressed regions and both with knownsubstrates/ligands. The pronounced conformational change in the dsDNAbound enzyme compared to apo enzyme lends further enthusiasm to thehypothesis that cGAS activity could be inhibited byappropriately-designed small molecules.

In an effort to identify drugs to block cGAS activity, we performed insilico screening of chemical and drug libraries using the publiclyavailable software, such as VINA™ and DOCK™. Using ComputationalAnalysis with the Autodock VINA™ platform, we identifiedhydroxychloroquine (HCQ), 9-amino-6-chloro-2-methoxyacridine andquinacrine to interact at the Zn thumb and spine regions of cGASinvolving simultaneous enzyme and DNA binding. The two main bindingevents, at the zinc thumb and at the spine, appear to occur within 3-10Angstroms of the amino acids shown by mutation to be needed for dsDNAbinding. The binding affinity was calculated by AutoDock VINA™ software.See Table 2.

Anti-malarial Drugs Inhibit DNA Binding to cGAS and dsDNA/cGAS ComplexFormation

To determine whether these anti-malarial drugs could inhibit DNA bindingto cGAS in vitro, we performed DNA binding studies by theelectrophoretic mobility shift assay (EMSA). As previously shown,addition of increasing concentrations of cGAS to a constantconcentration of ds DNA (ISD), results in the protein retardingmigration of ISD on the gel (‘gel shift’) and less free DNA (FIG. 1,left panel). To test whether HCQ as a model antimalarial could attenuatethe gel shift, we used constant concentrations of both ISD and cGAS(FIG. 1, right panel) in the presence of increasing concentrations ofHCQ. As shown, increasing the concentration of HCQ reduced the gel shiftcaused by the formation of dsDNA/cGAS complexes and led to increasingfree DNA at the bottom of the gel. This result indicates that HCQblocked dsDNA/cGAS binding. Inhibition of formation of dsDNA/cGAS higherorder complexes by antimalarial drugs are especially interesting andimportant since cGAS is activated by dsDNA induced oligomerization anddsDNA/cGAS complex formation is required for cGAS activation.

Antimalarial Drugs Differentially Inhibit cGAS Activity and cGAMPProduction

HCQ belongs to a family of antimalarial drugs that share the structureof aminoquinolines. To rapidly screen these antimalarial drugs for theirability to interfere with cGAS activation by ds-DNA, we performed dosetitration experiments with drug and quantified cGAMP production usingthin layer chromatography (TLC) (FIG. 2A). Reactions were performed intriplicate and normalized to no-inhibitor controls and fit by non-linearregression using Prism GRAPHPAD™ to determine the IC₅₀ of each compound.Each compound yielded dose-response curves similar to HCQ but withdifferent inhibitory activities (FIG. 2B). From these curves, weestimated the concentration of the test compound required for halfmaximal blockade of cGAS activity (IC₅₀, 50% inhibition coefficient). Asshown in FIG. 2C, Quinacrine and ACMA were relatively potent inhibitorsof cGAMP production; Primaquine and Quinine had very low inhibitoryactivity and both HCQ and Chloroquine had intermediate inhibitoryactivities. Strikingly, the computational predicted binding affinitiesof these anti-malaria drugs inversely correlated with the IC₅₀ ofanti-malarial drugs, validating the prediction of our computationalanalysis (FIG. 2D).

To test whether HCQ specifically inhibit cGAS activity but not STINGactivity, we incubated isotope labelled c-di-AMP with STING and thenadded un-labelled c-di-AMP or different concentration of HCQ. Ourresults demonstrated that HCQ could specifically block dsDNA binding tocGAS but not c-di-AMP to STING (FIG. 4).

Antimalarial Drugs could Inhibit IFNb Expression

Systemic Lupus Erythematosus (SLE) is strongly associated with increasedexpression of type I interferon (IFN-I) (Elkon, 2012). Both genetic aswell as experimental studies indicate that IFN-I plays a central role inthis disease (Lovgren, 2006) (Niewold, 2007). To determine thephysiological relevance of our computational analysis and in vitroobservance, we examined whether antimalarial drugs could inhibit IFNbproduction within the cell. As previously demonstrated by Sun and Wu etal (Sun, 2013) (Wu, 2013), cGAS is the cytosolic DNA sensor required forthe IFNb production in THP1 cells transfected with herring testis DNA.Using this approach, we transfected THP1 cells with DNA in the presenceor absence of antimalarial compounds and quantified IFNb expression byQPCR. As shown in FIG. 3. Quinacrine, AMCA, HCQ and Chloroquine allinhibited IFNb production by THP1 cells with an IC₅₀ dose range of 3-25μM. In contrast primaquine and Quinine were less effective by about onelog order IFNb (FIGS. 3A and 3B). Of note, the rank order ofantimalarials in vitro and in vivo was virtually identical validatingthe DNA/cGAS interaction as the target (compare FIG. 2B and FIG. 3B).

To rule out whether antimalarial drugs inhibited IFNb production byinterfering with transfection efficiency, we performed two experiments.First, we compared DNA transfection efficiency in the presence orabsence of antimalarial. In the second experiment, we preincubated THP1cells with antimalarial, washed the drug away and then evaluated theability of transfected drug to stimulate IFNb.

PolyIC was transfected by Lipofectamine to THP1 cells with differentconcentration of HCQ. The IL-1b cytokine production was measured byELISA and the results indicated HCQ did not interfere with theLipofectamine transfection efficiency (Supplemental FIG. 3).

The results demonstrated that some of antimalarial drugs could stronglyblock the interaction of DNA and cGAS and thus inhibit the IFNbproduction, which is a novel mechanism of antimalarial drugs' inhibitionof type I IFN production.

Materials and Methods

Computational Analysis

cGAS inhibitors were screened based on the crystal structure of the cGASand docking of compounds predicted in silico. In silico, structure-baseddrug screening were provided by AutoDock VINA™ and DOCK™.

cGAS Expression and Purification

Protein was expressed in Rosetta BL21 pLysS cells. 4.5 L of bacterialculture was induced at OD₆₀₀=0.5 with 500 μM IPTG and at 18° C. for 20hrs. Cells were lysed into 50 mM Tris-HCl, pH=8, 300 mM NaCl, 20 mMImidazole, 5 mM BME and 0.2 mM PMSF by sonication. Cleared lysate wasincubated with Ni-NTA, washed with 50 mL of Lysis buffer and eluted with20 mM Tris-Cl, pH=7.4, 300 mM NaCl, 500 mM Imidazole. Protein wassubsequently diluted to 200 mM NaCl and bound to a Heparin SEPHAROSE™column (GE Healthcare). The column was washed with 2 column volumes of250 mM NaCl, 20 mM Tris, 1 mM DTT, pH 7.4 and developed with a gradientfrom 250-1000 mM NaCl. The major peak of cGAS was finally purified usingan S200 SUPERDEX™ (GE Healthcare) size exclusion column with 20 mM TrispH 7.5, 250 mM NaCl and 1 mM DTT running buffer. Protein was ˜95% pureby Coomassie stained SDS-PAGE gel.

cGAS Activity Assays

Initial characterization of enzyme activity was monitored in thepresence of 250 μM ATP, 250 μM GTP, 0-500 μg/mL herring testes DNA, 1.4μM cGAS, 3.3 nM ³²P-γ-ATP in a buffer composed of 40 mM Tris, 250 mMNaCl, 10 mM MgCl2, pH 7.5. Reactions were incubated for 1 hr at roomtemperature and subsequently spotted on PEI-cellulose TLC plates anddeveloped using a solvent composition 1:1.5 [v/v] saturated NH4SO4 and1.5 M KH2PO4 [pH 3.6]. For inhibition assays, compounds werecharacterized in the presence of the above reaction contents at fixed100 μg/mL htDNA. TLC plates were exposed to a phosphor-storage screenand imaged using a TYPHOON™ imaging system. (See FIGS. 7-16).

cGAS activity was monitored in the presence of 250 μM ATP, 250 μM GTP,0-500 μg/ml herring testes DNA. 1.4 μM cGAS. and 3.3 nM [³²P]-ATP inTris buffer (pH 7.5). After incubation for 1 h at room temperature,samples were spotted on PEI-cellulose Thin Layer Chromatograph (TLC)plates, and developed using a solvent composed of 1:1.5 [v/v] saturatedNH₄SO₄ and 1.5 M KH₂PO₄ [pH 3.6]. For inhibition assays, compounds werecharacterized in the presence of the above reaction contents at fixed100 μg/ml HT DNA. TLC plates were exposed to a phosphor-storage screenand imaged using a TYPHOOON™ imaging system. (FIG. 7).

Thin Layer Chromatograph (TLC) assay was used for the quantification ofcGAS inhibition by compounds X5/X6/X7. Reactions were normalized tono-inhibitor controls and fit by non-linear regression using PrizmGRAPHPAD™ to determine the IC₅₀ of each compound. (FIG. 7).

Trex1−/− mouse were treated with 25 mg/kg/day compound X6 dissolved inwater with SPLENDA™ or water with SPLENDA™ only as control for 8 weeksfrom birth. At 8 weeks age, mice were sacrificed and spleens wereharvested. Mouse body mass and spleen mass were measured by balance.Statistical analysis was performed with a two-tailed, unpaired Student'st test. (FIG. 8).

Total RNA was isolated from heart or spleen tissues using the RNeasymini kit with a DNASE™ treatment step (Qiagen, Valencia, Calif.). cDNAwas generated using 300 ng RNA with the high-capacity cDNA RT-KIT™ usingrandom primers (Applied Biosystems, Foster City, Calif.). Reactions induplicate were run on an ABI ONESTEP PLUS™ using the different genespecific primers. A two-stage cycle of 95° C. for 15 s and 60° C. for 1min was repeated for 40 cycles followed by a dissociation stage.Threshold cycle values were set as a constant threshold at 0.2, and foldchanges in gene expression were then calculated using the 2^(−ΔΔ)CTmethod. (FIGS. 9, 10 and 11).

Heart were harvested when the mouse were sacrificed after 8 weekstreatment. RNA was isolated from heat tissues with RNEAST MINIKIT™ andcDNA was synthesized with the high-capacity cDNA RT-KIT™ using randomprimers. ISG15 and CXCL10 mRNA expression was normalized to the 18SmRNA. Horizontal bars represent the mean values. Statistical analysiswas performed with a two-tailed, unpaired Student's t test. (FIG. 9).

Spleen were harvested when the mouse were sacrificed after 8 weekstreatment. Spleen ISG15 and ISG20 mRNA expression was analyzed by qPCRand the results expressed relative to the 18S mRNA. Horizontal barsrepresent the mean values. Mean data was compared using a t test. (FIG.10).

Heart were harvested when the mouse were sacrificed after 8 weekstreatment. Heart IFNb mRNA expression was analyzed by qPCR and theresults expressed relative to the 18S mRNA. Horizontal bars representthe mean values. Mean data was compared using a t test. (FIG. 11).

Heart tissues were lysed with 80% MeOH spiked with 5 nM heavyisotope-labeled cGAMP (cGAMP*), containing ¹³C, ¹⁵N-perlabeled AMP, asinternal standard. Tissues extracts were sonicated on ice for 1 min with20% duty cycle and 1 output settings. Tissue debris was pelleted at14,000 rpm for 10 minutes. Methanol extraction solution was transferredto a new tube and evaporated using a speed vac. cGAMP was furtherpurified by Solid phase extraction column (OASIS WAX™ column fromWaters) and re-suspended in 50 ul OPTIMA LC/MS™ water (ThermalScientific, Odessa, Tex.) for Mass Spec analysis. For targeted detectionof cGAMP, a Multiple Reaction Monitoring (MRM) assay was developed onWaters XEVO TQS™ Mass Spectrometer coupled with Ultra-Performance LiquidChromatogram (UPLC). In the assay, two transitions of each target ionwere monitored: cGAMP, +675.1/152.1 (parent ion/daughter ion) and+675.1/136.0; cGAMP*, +690.0/152.1 and +690.0/146.0. (FIG. 12)

cGAMP was isolated from mouse heart tissues by a methanol extractionprocedure. The abundance of cGAMP was quantitated by mass spectrometryusing multiple reaction monitoring (MRM). Heavy isotope-labeled cGAMPwas spiked into each sample as an internal standard and the massspectrum of the internal standard was used to determine the peak of theendogenous cGAMP. cGAMP signal peak area was normalized to Heavy isotopelabelled cGAMP internal standards peak area. Mean data was comparedusing a t test. (FIG. 12).

Method for Pathology (FIG. 13, 14, 15, 16)

Trex1−/− mouse were treated with 25 mg/kg/day compound X6 dissolved inwater with SPLENDA™ or water with SPLENDA™ only as control for 8 weeksfrom birth. At 8 weeks age, mice were sacrificed and heart tissues wereharvested. Tissues were fixed in Formalin, paraffin embedded, cut into 5um sections, and stained with hematoxylin and eosin. All tissues werecoded to remove genotype identification and were evaluated for evidenceof inflammation and fibrosis. Numerical scores were assigned based ondegree of severity (0=normal to 5=most severe). The sum of individualscores from Endocardial Inflammation, Fibrosis and Myocardialinflammation was used to obtain a total tissue histological score.Scoring criteria for each tissue:

Endocardial Inflammation Score:

0=normal; I=few inflammatory cells; 2=multifocal clusters≤5;3=multifocal clusters≤10; 4=coalescing foci≥10; 5=coalescing to diffusefoci

Myocardial Inflammation:

0=normal; 1=few (1-3 cells); 2=multifocal foci (3-5) with degenerativechanges; 3=multifocal foci (3-5) with necrotic changes: 4=≥10 coalescingfoci

Endocardial Fibrosis:

0=normal; 1=few inflammatory cells: 2=multifocal clusters≤5,3=multifocal clusters≤10; 4=coalescing foci≥10; 5=coalescing to diffusefoci

Blinded analysis of heart tissues from Trex1−/− mouse treated withcompound X6 or SPLENDA™. Data are represented as total histologicalscores from individual animals as a sum of the scores from EndocardialInflammation, Endocardial Fibrosis and Myocardial changes. Horizontalbars represent the mean values. Statistical analysis was performed witha two-tailed, unpaired Student's t test. (FIG. 13).

Blinded analysis of heart tissues from Trex1−/− mouse treated withcompound X6 or SPLENDA™. Data are represented as histological scoresfrom individual animals for Endocardial Inflammation. Horizontal barsrepresent the mean values. Statistical analysis was performed with atwo-tailed, unpaired Student's t test. (FIG. 14).

Blinded analysis of heart tissues from Trex1−/− mouse treated withcompound X6 or SPLENDA™. Data are represented as histological scoresfrom individual animals for Endocardial Inflammation. Horizontal barsrepresent the mean values. Statistical analysis was performed with atwo-tailed, unpaired Student's t test. (FIG. 15).

Blinded analysis of heart tissues from Trex1−/− mouse treated withcompound X6 or SPLENDA™. Data are represented as combined histologicalscores from individual animals as a sum of the scores from EndocardialInflammation and Fibrosis. Horizontal bars represent the mean values.Statistical analysis was performed with a two-tailed, unpaired Student'st test. (FIG. 16)

Electrophoretic Mobility Shift Assays (EMSA)

Electrophoretic mobility shift assay (EMSAs) were performed to measurethe DNA-binding ability with or without HCQ in vitro. For the DNAbinding studies, 0.2 μM of the 100 bp annealed double strandedinterferon stimulatory DNA (ISD) (Forward:5′-ACATCTAGTACATGTCTAGTCAGTATCTAGTGATTATCTAGACATACATCTAGTACATGTCTAGTCAGTATCTAGTGATTATCTAGACATGGACTCATCC-3′, Backward5′-GGATGAGTCCATGTCTAGATAATCACTAGATACTGACTAGACATGTACTAGATGTATGTCTAGATAATCACTAGATACTGACTAGACATGTACTAGATGT-3′) were mixed 1.5 μM cGASprotein and different concentration of HCQ (0.075˜5 mM) and incubated inRT for 2 hours. The mixtures were resolved on 1% agarose gel using 1×TBEelectrophoresis buffer of at constant voltage of 100 V. The gel wasanalyzed by using a fluorescence-based EMSA kit (Molecular Probes)according to the manufacturer's protocol. Gels stained with fluorescentdyes were visualized by a Gel Doc XR™ (Bio-Rad).

THP1 Cell Stimulation and IFNb Expression Inhibition

THP1 cells (0.2×10⁶) were transfected with 0.5 ug herring testis DNAusing Lipofectamine 2000 (Invitrogen) according to the manufacture'sinstruction. Before transfection, THP1 cells were incubated withdifferent concentration of Hydroxychloroquine or other antimalarialdrugs (100, 50, 25, 12.5 μM) for 5 minutes. Cells were stimulated for 16hours and then harvested for RNA extraction.

RNA Preparation and Quantitative Real-time PCR

Total RNA was isolated from THP1 cells using the RNeasy mini kit(Qiagen, Valencia, Calif.). cDNA was synthesized using 100 ng RNA withthe high-capacity cDNA RT-KIT™ using random primers (Applied Biosystems,Foster City, Calif.). Reactions in duplicate were run on an ABI STEPONEPLUS™ using the primers from Qiagen (primer catalog number): a two-stagecycle of 95° C. for 15 s and 60° C. for 1 min was repeated for 40 cyclesfollowed by a dissociation stage. Threshold cycle values were set as aconstant threshold at 0.2, and fold changes in gene expression were thencalculated using the 2^(−ΔΔ) ^(CT) method.

Example 2

The Second Messenger, cGAMP, and the Enzyme, cGAS, are Expressed inSystemic Lupus Erythematosus

To determine whether the cGAS pathway could contribute to IFN productionin SLE, cGAS expression was quantified by QPCR from RNA obtained from 51SLE and 20 Normal Control peripheral blood mononuclear cells (PBMC).These studies revealed that SLE patients had a significant increase inthe expression of cGAS (P=0.0045). cGAS expression positively correlatedwith ISG expression and IFN score in SLE patients consistent with itbeing an IFN signature gene.

To determine whether downstream pathways of cGAS were activated in SLEcells, IRF3 activation was quantified by phosphorylation in PBMC. IRF3was activated in a higher proportion of SLE patients compared tocontrols. These findings suggest that the cGAS pathway appears active inSLE patients and likely contributes to IFN stimulation regardless ofwhether upregulation of cGAS is an initiator of IFN-I stimulation or isa consequence of IFN-I stimulation. To quantify c-GAMP in patientsamples we have obtained cyclic GMP-AMP dinucleotide that is comprisedof the unusual 2′-5′ and 3′-5′ phosphodiester linkage and have been ableto distinguish the cyclic dinucleotide from other species by HighPerformance Liquid Chromatography-tandem Mass Spectrometry (HPLC-MS/MS).cGAMP is expressed in approximately one third of SLE patients withhigher anti-DNA antibody titer. Experiments were conducted to determinewhether cGAS and cGAMP can be used as a biomarker of SLE activity thatcorrelates with disease activity, duration or severity. AutoDock VINA™was used to identify several drugs including Hydroxychloroquine thatinteracts at the Zn thumb and spine regions of cGAS involvingsimultaneous protein and DNA binding. EMSA analysis shows that HCQinhibits the DNA binding to cGAS, which suggests a possible mechanism ofHCQ action through the interruption of dsDNA stimulated cGAS enzymeactivation besides the HCQ inhibition of lysosome acidification.

IFN-β can be produced by almost any cell following stimulation by (viralor bacterial) nucleic acids. Release of this cytokine serves to prime oramplify type I IFN by other cells. especially plasmacytoid dendriticcells (pDCs) that are the main producers of IFN-α. Over the last decade,there have been major advances in the understanding of the role ofintracellular sensors such as Toll Like Receptors (TLRs), RIG-I likereceptors (RLRs) and Aim-like receptors (ALRs) that respond to nucleicacid ligands by stimulating production of IFN-I and other inflammatorycytokines (Takeuchi, O. and S. Akira, Pattern recognition receptors andinflammation. Cell, 2010. 140(6): p. 805-20). Cyclic di-nucleotides werediscovered in bacteria more than 25 years ago and are known to functionas ubiquitous second messenger molecules that regulate motility, biofilmformation, and virulence. Recently, it was reported that cyclic di-AMP(c-di-AMP) produced by bacteria could stimulate the production of IFN-Iby the cytosolic surveillance pathway (CSP) (Woodward, J. J., A. T.Iavarone, and D. A. Portnoy, c-di-AMP secreted by intracellular Listeriamonocytogenes activates a host type I interferon response. Science,2010. 328(5986): p. 1703-5). Further dissection of the pathway revealedthat c-di-GMP bound to and activated the adaptor, STING (Burdette, D.L., et al., STING is a direct innate immune sensor of cyclic di-GMP.Nature, 2011. 478(7370): p. 515-8) which was previously identified as aDNA sensor in the CSP resulting in the stimulation of IFN-b. Morerecently, Chen et al (Wu, J., et al., Cyclic GMP-AMP is an endogenoussecond messenger in innate immune signaling by cytosolic DNA. Science,2013. 339(6121): p. 826-30) discovered that a cyclic GMP-AMP (cGAMP) wasproduced in metazoans and that it also stimulated IFN-I in mammaliancells. In brief, ds-DNA binds to a positively charged pocket of theenzyme, cyclic GAMP synthase (cGAS) (Sun, L., et al., Cyclic GMP-AMPsynthase is a cytosolic DNA sensor that activates the type I interferonpathway. Science, 2013. 339(6121): p. 786-91). This binding results in aconformational change and opening of a catalytic cleft resulting in thesynthesis of the noncanonical cyclic dinucleotide, cyclic GMP-AMP(cGAMP) containing an unusual [G(2′-5′)pA(3′-5′)p] linkage (Diner, E.J., et al., The Innate Immune DNA Sensor cGAS Produces a NoncanonicalCyclic Dinucleotide that Activates Human STING. Cell Rep. 2013. 3(5): p.1355-61) cGAMP binds to the adaptor protein, STING, which triggersactivation of TBK. IRF3 and IFN-b (Sun, 2013). Our goal was to determinewhether the second messenger, cGAMP, plays a role in the disease SLEthat is characterized by an IFN signature.

Increased Expression of cGAS and pIRF3 in a Proportion of SLE Patients

QPCR analysis of cGAS expression from healthy controls (CNT, n=20) andSLE (n=51). Samples were normalized for expression of 18S ribosomal RNA.A highly statistically significant difference in expression was observedbetween SLE patients and controls. cGAS expression correlated well withIFN score in SLE patients (FIG. 5B). Western blot assay for thephosphorylated IRF3 expression. PBMC were obtained from 10 SLE patients,13 RA patients and healthy controls. Proteins were resolved by SDS-PAGE,blotted to nitrocellulose and probed with an antibody to phosphorylatedIRF3. The blot was stripped and reprobed with antibody to b-actin toensure equal loading. A representative blot is shown in FIG. 5C. From invitro studies, it has been shown that stimulation of TLR7/9 by ICendocytosed from blood or tissue contribute to the IFN signatureobserved in human SLE. There is precedent for cell intrinsic stimulationof IFN-I by DNA in the Aicardi-Goutierre's Syndrome (AGS) and a subsetof SLE patients (Lee-Kirsch, M. A., et al., Mutations in the geneencoding the 3′-5′ DNA exonuclease TREX1 are associated with systemiclupus erythematosus. Nat Genet, 2007. 39(9): p. 1065-7: Namjou, B., etal., Evaluation of the TREX1 gene in a large multi-ancestral lupuscohort. Genes Immun, 2011. 12(4): p. 270-9). We therefore explored theidea that cGAS was implicated in the initiation or perpetuation of IFNstimulation in SLE. We first tested cGAS expression in SLE patients.QPCR obtained from 51 SLE patients and 20 normal controls, revealedthat, indeed, cGAS expression was significantly increased in SLEpatients compared to normal controls (FIG. 5A). The IFN score and cGASexpression were highly correlated (FIG. 5B). Since cGAS (c6ORF150) is anIFN response genes (ISG) (Schoggins, J. W., et al., A diverse range ofgene products are effectors of the type I interferon antiviral response.Nature, 2011. 472(7344): p. 481-485), this finding could indicate thatcGAS is elevated as a consequence of exposure to IFN-I and/or that cGASmay be induced by an unknown DNA stimulus which then primes for enhancedIFN-I responses in a positive feedback cycle.

cGAS synthesis of cGAMP leads to direct binding and activation of STINGwhich, in turn, causes activation of IRF3 in a TBK dependent pathway.When IRF3 is activated, it becomes phosphorylated, dimerizes andtranslocates to the nucleus where it exerts its transcriptional functionleading to upregulation of IFN-b (Akira, 2010). We therefore testedwhether IRF3 was activated in PBMC from SLE patients. As shown in FIG.5C, when randomly selected SLE, rheumatoid arthritis (RA) and normalPBMC were tested for IRF3 activation, IRF3 phosphorylation was observedin 6 out of 10 SLE patients PBMC but only 2 out of 13 control samples(p=0.028, Fishers exact test). The finding that IRF3 was activated inPBMC from a proportion of SLE patients strongly indicates that thissecond messenger pathway is active.

GAS is Functional and cGAMP is Expressed in SLE Patients

THP1 cells were transfected with HT-DNA. cGAMP were purified from THP1cells, SLE patients PBMC and their controls as described in the methodssection. The abundance of cGAMP was quantitated by mass spectrometryusing SRM. Note that the peak in the SLE cells is derived from m/z ofthe daughter ions of m/z 673.1 corresponding to cGAMP. This result ispivotal because it proves that not only is the expression of cGASincreased, but also that the enzyme is functional in SLE patient cellsand implies activation by DNA. B. cGAMP were purified from PBMC of SLEpatients (n=13), RA patients (n=3) and healthy controls (n=6). Thepresence of cGAMP was measured by mass spectrometry using SRM.

Activation of IRF3 could result from stimulation by cGAS or by otherpathways such as TLR4, RIG-I or MDA5. To definitively determine whetherthe cGAS pathway was active in SLE patients, we sought to determinewhether cGAMP was expressed in PBMC. We first optimized methods anddetected cGAMP in DNA transfected (as well as HSV infected) THP1 cellsbut not in un-transfected THP1 cells (FIG. 6A). When we tested SLE andhealthy control PBMCs, we detected the dinucleotide at exactly 3 minutesin the SLE patient, but not control sample. Note that the peak isderived from m/z of 673.1 corresponding to cGAMP. This result is pivotalbecause it proves that cGAS in SLE patient cells is functional. We thenrandomly selected 13 SLE, 6 normal controls and 3 rheumatoid arthritispatients and tested their PBMC for cGAMP expression by LC/MS/MS. Ofthese 22 samples, 4/13 (31%) SLE, but none of the 9 controls werepositive (FIG. 6B). Thus cGAMP is produced in the cells of approximatelyone third of SLE patients. DNA ICs have been shown to stimulate IL-b inmonocytes.

Clinical Features of SLE Patients with cGAS Expression

To determine what clinical, therapeutic or other properties mightdistinguish those that do and do not express cGAMP, the duration ofdisease is examined as we postulated that activation of the cGAS pathwaymay prime cells such as pDC for IFN-a responses. To determine whetherdrug therapy could explain suppression of cGAMP in about two thirds ofpatients, hydroxychloroquine, corticosteroid and other therapies arecompared. The severity of disease are explored by examining the SLEDAIin each patient.

Materials and Methods

RNA Preparation and Quantitative Real-time PCR

Total RNA was isolated from peripheral mononuclear cells (PBMC) ofnormal and SLE patients' blood using the RNEASY MINI KIT™ with on columnDNASE™ treatment (Qiagen, Valencia, Calif.). cDNA was generated using 25ng RNA with the high-capacity cDNA RT-KIT™ using random primers (AppliedBiosystems, Foster City, Calif.). Reactions in duplicate were run on anABI STEPONE PLUS™ using cGAS forward primer and backward primer; atwo-stage cycle of 95° C. for 15 s and 60° C. for 1 min was repeated for40 cycles followed by a dissociation stage. Threshold cycle values wereset as a constant threshold at 0.2, and fold changes in gene expressionwere then calculated using the 2^(−ΔΔ) ^(CT) method.

Western Blot

Cells were lysed in RIPA buffer (25 mM Tris-HCl pH 7.6, 150 mM NaCl, 1%NP-40, 1% sodium deoxycholate, 0.1% SDS) with IX protease inhibitors andphosphatase inhibitors cocktail (Thermal Scientific. Odessa, Tex.), and20 μg protein from each sample was used for Western blot. The dilutionof anti-pIRF3 was 1:500 (Cell Signalling, Danvers, Mass., USA), thedilution of anti-actin was 1:5000 (Santa Cruz Biotechnology, Santa Cruz,Calif., USA). Signals were detected using the ECL™ detection system andfilm (GE Healthcare, Piscataway, N.J. USA). The quantitation was carriedout using FLUORCHEM™ imaging system and software (Alpha Innotech, SanLeandro, Calif., USA) with normalizing on the intensity of β-actin.

DNA Stimulation for cGAMP Production

THP1 cells were seeded 35M cells in 35 ML medium at the time oftransfection in T175 cell culture flask. 90 ug DNA was diluted in 1.75ml Serum free medium and 230 ul LIPOFECTAMINE 2000™ reagent was dilutedin 1.75 ml serum free medium. Then diluted DNA was added to the tube ofdiluted LIPOFECTAMINE 2000™ reagent in 1:1 ratio. The DNA andLIPOFECTAMINE™ mixture was incubated for 5 mins at RT and thenDNA-regent complex was added to the cells. The transfected cells werecultured in 37 C. incubator for 2 days and then harvested for the cGAMPpurifications.

cGAMP Purification

The cells were lysed with NER™ lysis buffer from NE-PER Nuclear andCytoplasmic Extraction kits (Thermal Scientific, Odessa, Tex.) accordingto the instruction for the cell volumes vs NER volumes. Spin down thenuclei (˜16,000 g for 5 min), take the supernatant and mix this withphenol with 1:1 ratio. Mix, incubate on ice for 5 min, centrifuge for 5min at 16,000 g at 4° C. Take the upper phase and mix with 2× volumeschloroform. Mix, incubate for 5 min, centrifuge for 5 min at 16,000 g at4° C. Take the upper phase and transfer it to a molecular weight cut-offcolumn (10,000 MW). Spin as indicated and collect the flow-through. Theflow-through was dried by SPEEDVAC™ and resuspended in 20 ul OPTIMALC/MS™ water (Thermal Scientific, Odessa, Tex.). This was loaded on theHPLC column for Mass Spec analysis.

cGAMP Measurement by UPLC-MS/MS

High resolution mass measurement and tandem MS/MS is performed on WatersXEVO TQS™ Mass Spectrometer coupled with Ultra-Performance LiquidChromatogram (UPLC). Full scan mass spectra are acquired form m/z200-800. MS/MS spectra are acquired and the top five most abundant ionssubjected to further fragmentation by collision induced dissociation(CID). For targeted quantification of cGAMP, a selective reactionmonitoring (SRM) assay was developed on the XEVO TQS™ mass spectrometer.In the assay, three transitions of each target ion are monitored. Theparent ion is isolated at m/z 673.1 in a negative mode (M−H)−,fragmented while the resulting daughter ion is monitored at m/z 341.10,150.05, and 133.93 in a negative mode (M−H)−.

Example 3

Targeted Therapy to Inhibit cGAS Stimulated Type I IFN Production

In an effort to identify drugs to block cGAS activity, we performed insilico screening of chemical and drug libraries and identified acandidate, HCQ, predicted to interact strongly with cGAS. HCQ is FDAapproved and has a favorable safety profile.

The compound of Formula (I),

wherein R₁ is selected from Cl, OH, NH₂, and NO₂; R₂ is selected from

and n is 3 or 4.

The compounds of Formula (I) potently inhibit cGAS resulting in reducedproduction of IFN-I in lupus as well as autoimmune diseases such asscleroderma, polymyositis and possibly type 1 diabetes that have beenassociated with increased IFN I.

The design of the compound of Formula (I) started with theenergy-minimized structures of X-cGAS and DNA-X-cGAS complexes.Preliminary in silico studies have already identified two potentialbinding sites that are likely responsible for the blocking of thecrucial DNA-cGAS interactions. The compound of Formula (I) has anincreased affinity to cGAS while preventing DNA interaction with cGAS.Compounds of Formula (I) were be chemically synthesized and evaluatedfor binding to cGAS and for their ability to block the formation ofDNA-cGAS complexes. They were also tested in cell-based assays (THP-1production of IFN-b by QPCR) for production of IFN-I. The most promisingdrug candidates were tested in animal models of lupus and AGS. Compoundsof Formula (I) non-toxic to cells were tested in AGS mouse model andlupus mouse model compared with quinacrine (QC) or HCQ as controls. Insome aspects the AGS mouse model is TREX1−/−. In some aspects the lupusmouse model is NZB/W.

Synthesis

N,N′-Dimethyl-N′-(6-nitro-2-methoxy-acridin-9-yl)-N-benzylpropane-1,3-diamine(R1=NO2, R2=benzyl, n=3). 6-Nitro-2-methoxy-9-chloroacridine (288 mg, 1mmol){Csuk, 2004 #3231} is reacted with N,N′-dimethyl-N-benzylpropane1,3-diamine (192 mg, 1 mmol) in phenol (10 mL) for 5 hrs at 110° C.After cooled to room temperature, the reaction mixture is diluted withdichloromethane. The mixture is washed twice with sodium hydroxidesolution (IN) and twice with ammonium chloride solution. The organiclayer is separated, dried over anhydrous sodium sulfate, andconcentrated. The residue is purified by silica gel chromatography usingtriethylamine (5%) and methanol (5 to 15%) in dichloromethane to givethe desired compound.

N,N′-Dimethyl-N′-(6-nitro-2-methoxy-acridin-9-yl)-N-(4-pyridyl)propane-1,3-diamine(R1=NO2,R2=4-pyridyl, n=3). Essentially the same reaction as above is carriedout by using 6-Nitro-2-methoxy-9-chloroacridine andN,N′-dimethyl-N-(4-pyridyl)propane 1,3-diamine.

N,N′-Dimethyl-N′-(6-nitro-2-methoxy-acridin-9-yl)-N-(2-furanyl)propane-1,3-diamine(R1=NO2,R2=2-furanyl, n=3). Essentially the same reaction as above is carriedout by using 6-Nitro-2-methoxy-9-chloroacridine andN,N′-dimethyl-N-(2-furanyl)propane 1,3-diamine.

A hot (60° C.) solution of SnCl2-2H2O (3.5 mol/mol of nitro group) in12N HCl—AcOH (1:1 v/v) (2 mL/g of SnCl2-2H2O) is added in one portion tofinely powdered nitro acridine compound contained in an larger flask.The initial vigor of the reaction is moderated by cooling in tap water.It is essential that at some stage in the reaction a clear solution isobtained. When the vigorous reaction abated the mixture is boiled underreflux for 1.5 hr. After cooling to room temperature, HCL is added toprecipitate the crude product. The crude product is dissolved in hot 0.2N HCl, filtered, and added 12N HCl to precipitate the pure material. Thesame general method is used to produce the following three compounds; N,N′-Dimethyl-N′-(6-amino-2-methoxy-acridin-9-yl)-N-benzylpropane-1,3-diamine(R1=NH2, R2=benzyl, n=3), N,N′-Dimethyl-N′-(6-amino-2-methoxy-acridin-9-yl)-N-(4-pyridyl)propane-1,3-diamine(R1=NH2,R2=4-pyridyl, n=3), and N,N′-Dimethyl-N′-(6-amino-2-methoxy-acridin-9-yl)-N-(2-furanyl)propane-1,3-diamine(R1=NH2,R2=2-furanyl, n=3).

Example 4

Targeted Therapy to Inhibit cGAS Stimulated Type I IFN Production

The compound of Formula (I),

wherein R₁ is H, Cl, OH, NH₂ or NO₂; R₂ is H or —OCH₃; R₃ and R₄ are Hor CH₃; R₅ and R₆ are H, CH₃, —CH₂CH₂SH,

and n is 2 or 3.

The compounds of Formulae (I), (II) and (III) potently inhibit cGASresulting in reduced production of IFN-I in lupus as well as autoimmunediseases such as scleroderma, polymyositis and possibly type 1 diabetesthat have been associated with increased IFN I.

Example 5

Synthesis of Compounds of Formulae (I)-(III)

9-Chloro-3-nitro-7-methoxyacridine

9-Chloro-3-nitro-7-methoxyacridine was prepared in two steps accordingto the published procedure.

9-Chloro-3-amino-7-methoxyacridine

In a 10 mL round bottom flask were placed9-chloro-3-nitro-7-methoxyacridine (0.1 gram, 3.46×10⁴ mole), Fe powder(58 mg, 1.04×10⁻³ mole), EtOH (0.5 mL), AcOH (2 mL) and H2O (10 μL).Yellow starting material appeared largely insoluble and suspended. Put aglass cap on the flask. Sonicated the mixture at 30˜45° C. (started at30° C. and the bath temperature gradually increased during thesonication) for 50-min, 15 min-break and another 50-min. The solutionturned to a deep red color at the end of reaction. Filtered the reactionmixture through a small glass filter to remove excess iron. Theinsoluble residues were washed with EtOH—AcOH (1:1) and then EtOH. Thefiltrate and washings were combined and concentrated under vacuum toapproximately 1˜2 mL. To the viscous red residues, 12NHCl (2 mL) wasadded, and sonicated briefly. The oily residues turned into solid, andwere collected by centrifugation. The products were dried under vacuum.Yield: 0.138 gram (quantitative yield). ESI-MS: m/z=259.1 ([M+H]⁺).

N, N′-Dimethyl-N-benzyl-1,3-propanediamine (X5 arm)

The compound was prepared according to the published procedure. Benzylchloride (2.0 mL, 0.017 mole) was added drop-wise into a refluxingsolution of N, N′-dimethyl-1,3-propanediamine (3.2 mL, 0.026 mole)dissolved in 20 mL THF. White precipitates appeared as the benzylchloride was added gradually over 30-min. After the addition iscomplete, the reaction mixture was kept refluxing for another 1 hr. Thereaction mixture was then cooled to room temperature, 1M NaOH solutionwas added and extracted with CH2Cl2. The organic layer was collected,dried over anhydrous Na2SO4, and concentrated. The product was isolatedby distillation under reduced pressure. The product boiled at 75˜80° C.(0.1 mmHg). Yield 1.29 g (40%).

N, N′-Dimethyl-N-(4′-pyridylmethyl)-1,3-propanediamine (X6 arm)

4-chloromethylpyridine HCl (2.79 gram, 0.017 mole) is neutralized with20 mL of 1M NaOH on an ice bath, and extracted with CH2Cl2 three times.The CH2Cl2 layers were combined and dried over anhydrous Na₂SO₄. Thesolvent was evaporated, and the residues were re-dissolved in 5 mL THF.The THF solution was used immediately for the synthesis.

A solution of N, N′-dimethyl-1,3-propanediamine (3.2 mL, 0.026 mole) in15 mL THF was brought to reflux, and the THF solution of4-chloromethylpyridine was added dropwise over 30-min. After theaddition, the dropping funnel was washed with 5 mL THF. After theaddition is complete, the reaction mixture was kept refluxing foranother 1 hr. White precipitates were formed. The reaction mixture wasthen cooled to room temperature, and the solvent was removed undervacuum. To the residue was added 1M NaOH, and the product was extractedCH2Cl2 three times. The organic layers were combined, and dried overanhydrous Na2CO3. The CH2Cl2 solution was concentrated, and the productwas isolated by distillation under reduced pressure. The product boiledat 90˜95° C. (0.1 mmHg), Yield 1.33 gram (41%). ¹H-NMR (300 MHz, CDCl₃):δ (ppm) 8.54 (2H, d), 7.26 (2H, d), 3.48 (2H, s), 2.62 (2H, t), 2.41(3H, s), 2.41 (2H, t), 2.20 (3H, s), 1.70 (2H, quintet), 1.51 (1H, br.s).

N, N′-Dimethyl-N-furfuryl-1,3-propanediamine (X7 arm)

Furfuryl chloride (2.0 mL, 0.017 mole) was added drop-wise into arefluxing solution of N, N′-dimethyl-1,3-propanediamine (3.2 mL, 0.026mole) dissolved in 20 mL THF. White precipitates were observed asfurfuryl chloride was added gradually over 30-min. After the addition iscomplete, the reaction mixture was kept refluxing for another 1 hr. Thereaction mixture was then cooled to room temperature, 1M NaOH solutionwas added, and extracted with CH2Cl2. The organic layers were combined,dried over anhydrous Na2SO4 and concentrated. The product was isolatedby distillation under reduced pressure. The product boiled at 60-65° C.(0.1 mmHg). Yield 1.16 g (37%). ¹H-NMR (300 MHz, CDCl₃): δ (ppm) 7.37(1H, m), 6.31 (1H, m), 6.17 (1H, m), 3.55 (2H. s), 2.61 (2H, t), 2.40(3H. s), 2.40 (2H, t), 2.24 (3H, s), 1.70 (2H, quintet), 1.84 (1H, br.s).

9-(N-(4″-pyridylmethyl)-N-methyl-N′-methyl-1′,3′-propanediamine))-3-amino-7-methoxyacridine(X6)

The dark red powder of crude 9-Chloro-3-amino-7-methoxyacridine preparedfrom 0.2 gram of the corresponding nitro compound was placed in 50 mLflask, and added 2 mL of EtOH, X6 arm (0.25 gram) and triethylamine (300μL). The mixture was sonicated briefly to make a suspension, and thenheated to reflux on an oil bath. The reflux was continued with stirringfor 5 hrs. The solvent was removed under vacuum. The residues weredissolved in 10 mL CH2Cl2 with sonication. Some insoluble materials werevisible. Apply the whole suspension to a silica gel column (12 g inCH2Cl2). The column was washed with 50 mL CH2Cl2, and then eluted with9:1:0.1 (CH2Cl2, MeOH, NH4OH) 100 mL. Collected the dark red fraction,and concentrated with under vacuum. The residues were dried under vacuumovernight. Yield 0.39 gram. The crude material was dissolved in DMF andpurified by HPLC, C18 reverse phase and a standardacetonitrile-water-0.1% TFA linier gradient. The purified X6 waslyophilized to produce orange powder. ESI-MS: m/z=416.3 ([M+H]⁺).

9-(N-benzyl-N-methyl-N′-methyl-1′,3′-propanediamine)-3-amino-7-methoxyacridine(X5)

X5 was prepared by the same procedure as for X6 by using X5 arm. ESI-MS:m/z=415.5 ([M+H]⁺)

9-(N-furfuryl-N-methyl-N′-methyl-1′,3′-propanediamine)-3-amino-7-methoxyacridine(X7)

X7 was prepared by the same procedure as for X6 by using X7 arm. ESI-MS:m/z=405.2 ([M+H]⁺)

9-(N-(4″-pyridylmethyl)-N-methyl-N′-methyl-1′,3′-propanediamine))-3-n-butoxyamino-7-methoxyacridine(C6X6)

X6 (5 mg, 1.2×10-5 mole) was suspended in 1 mL CH2Cl2, and triethylamine(8.4 μL, 6×10-5 mole) was added. Slight color changes occurred fromorange to yellow. Sonicated the mixture for 1 min, and n-hexanoylchloride (3.4 μL, 2.4×10-4 mole) was added by using a 10 uL syringe.White fume appeared. The yellow color intensified with disappearance ofsuspended small particles of X6. The mixture was kept at roomtemperature. The color changed to yellow-green after 2 hrs. HPLC showeda major peak that appears to be more hydrophobic than X6. The reactionwas then quenched by adding 50 uL of methanol. The product was purifiedby C18 reverse phase HPLC with a standard acetonitrile-water-0.1% TFAgradient. Yield 6.4 mg (100%). ESI-MS: m/z=524.4 ([M+H]⁺)

9-(N-(4″-pyridylmethyl)-N-methyl-N′-methyl-1′,3′-propanediamine))-3-trifluoroacetylamide-7-methoxyacridine(TFAX6)

9-(N-(4″-pyridylmethyl)-N-methyl-N′-methyl-1′,3′-propanediamine))-3-benzamide-7-methoxyacridine(BzX6)

9-(N-(4″-pyridylmethyl)-N-methyl-N′-methyl-1′,3′-propanediamine))-3-ethoxycarbonyl-7-methoxyacridine(ETOX6)

TFAX6, BzX6 and ETOX6 were prepared by using the same procedure as thatfor C6X6, starting from purified X6 and trifluoroacetic anhydride,benzoyl chloride or chloroethylcarbonate as an acylating agent,respectively. The reaction product was purified by reverse phase HPLC,and the product was more hydrophobic than X6.

TABLE 1 IC₅₀ Data IC₅₀ Enzyme Assay Toxicity¹ No. Structure (μM) (μM)  1(HCQ)

   350 —  2 (CQ)

   850 —  3 (PQ)

   850 —  4 (QC/QQ)

   13 33.0  5 (QN)

  2000 —  6 (AMCA QQore)

   32 —  7

   10 —  8

    5 —  9

 >650 — 10

 >650 — 11

 >650 — 12

 >650 — 13    18 33.1 (X5) 14    23 27.4 (X6) 15    35 — (X7) 16 (C6X6)

— — 17 (TFAX6)

— — 18 (BzX6)

— — 19

— — 20

    8 — 21

    1 16.0 ¹Average of 3 cell lines @ 50% cell death

TABLE 2 AutoDock VINA ™ PDB PDB PDB 4K97 4K98 4LEZ (mcGAS + (mcGAS + PDB(mcGAS + dsDNA dsDNA 4K8V dsDNA MONOMER MONOMER (mCGAS DIMER C A NOdsDNA dsDNA SITE II) CHAIN) CHAIN) dsDNA) (EF) (IJ) No. ΔG ΔG ΔG ΔG ΔGΔG 1 −7.0 −5.7 −6.4 −5.2 −6.4 −6.3 2 −6.7 −5.8 −5.9 −5.1 −6.2 −6.2 3−6.8 −5.7 −6.7 −5.3 −6.2 −6.0 4 −8.0 −6.8 −6.0 −5.2 −6.9 −6.4 5 −8.2−6.6 −7.2 −5.7 −7.0 −7.1 6 −7.7 −7.1 −7.3 −5.9 −7.2 −6.8 7 −8.2 −7.2−7.6 −6.2 −7.1 −6.8 8 −7.3 −6.5 −6.6 −5.7 −6.8 −6.3 9 −9.3 −8.1 −8.1−6.9 −8.4 −7.9 10 −8.8 −8.5 −7.5 −6.4 −7.1 −7.2 11 −9.3 −8.6 −7.7 −6.7−7.5 −7.5 12 −8.5 −7.5 −8.0 −6.2 −7.5 −7.5 13 −9.5 −6.2 −7.2 −5.5 −7.4−7.3 14 −9.0 −7.9 −7.3 −6.1 −7.7 −7.3 15 −9.2 −8.1 −7.4 −5.1 −7.4 −7.520 −7.8 −7.0 −7.0 −5.4 −7.3 −7.3 21 −7.5 −6.7 −6.8 −6.6 NA −7.5

What is claimed:
 1. A compound of Formula (I) or a prodrug thereof,

wherein R₁ is —OH, —NH₂, —N(H)C(O)R₇ or —NO₂; R₂ is —H or —OCH₃; R₃ andR₄ are independently —H or —CH₃; R₅ and R₆ are independently —H, —CH₃,—CH₂CH₂SH,

R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₂CH₃, —CF₃,—CH₂CF₃ or

 and n is 2 or
 3. 2. The compound of claim 1, wherein R₁ is —NH₂ or—N(H)C(O)R₇; R₂ is —OCH₃; R₃ is —CH₃; R₄ is —H; R₅ is —CH₃; R₆ is

R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₂CH₃, —CF₃,—CH₂CF₃ or

 and n is
 2. 3. The compound of claim 1, wherein R₁ is —NH₂ or—N(H)C(O)R₇; R₂ is —OCH₃; R₃ is —CH₃; R₄ is —H; R₅ is —CH₃; R₆ is

R₇ is —OCH₂CH₃, —CH₂CH₂CH₂CH₂CH₃, —CF₃ or

 and n is
 2. 4. The compound of claim 1, wherein R₁ is —NH₂; R₂ is—OCH₃; R₃ is —CH₃; R₄ is —H; R₅ is —CH₃; R₆ is

 and n is
 2. 5. The compound of claim 2, wherein R₁ is —NH₂; R₂ is—OCH₃; R₃ is —CH₃; R₄ is —H; R₅ is —CH₃; R₆ is

 and n is
 2. 6. The compound of claim 2, wherein R₁ is —NH₂; R₂ is—OCH₃; R₃ is —CH₃; R₄ is —H; R₅ is —CH₃; R₆ is

 and n is
 2. 7. The compound of claim 2, wherein R₁ is N(H)C(O)R₇. 8.The compound of claim 2, wherein R₁ is —N(H)C(O)R₇; R₂ is —OCH₃; R₃ is—CH₃; R₄ is —H; R₅ is —CH₃; R₆ is

 and n is
 2. 9. The compound of claim 2, wherein R₁ is—N(H)C(O)CH₂CH₂CH₂CH₂CH₃; R₂ is —OCH₃; R₃ is —CH₃; R₄ is —H; R₅ is —CH₃;R₆ is

 and n is
 2. 10. The compound of claim 2, wherein R₁ is —N(H)C(O)CF₃; R₂is —OCH₃; R₃ is —CH₃; R₄ is —H; R₅ is —CH₃; R₆ is

 and n is
 2. 11. The compound of claim 2, wherein R₁ is —N(H)C(O)R₇; R₂is —OCH₃; R₃ is —CH₃; R₄ is —H; R₅ is —CH₃; R₆ is

R₇ is

 and n is
 2. 12. A compound of Formula (II) or a prodrug thereof,

wherein R₁ is —Cl, —OH, —NH₂, or —NO₂; R₆ is

 and n is 3 or
 4. 13. A compound of Formula (I) or a prodrug thereof,

wherein R₁ is —H, —Cl, —OH, —NH₂ or —NO₂; R₂ is —H or —OCH₃; R₃ and R₄are independently —H or —CH₃; R₅ and R₆ are independently —H, —CH₃,—CH₂CH₂SH,

 and n is 2 or
 3. 14. The compound of claim 13, wherein R₁ is —NH₂; R₂is —OCH₃; R₃ is —CH₃; R₄ is —H; R₅ is —CH₃; R₆ is

and n is
 2. 15. A pharmaceutical composition comprising a compound ofclaim 1 and a pharmaceutically acceptable carrier, diluent or excipient.16. A method for the treatment of an autoimmune disease or a monogenicdisorder, the method comprising administering an effective amount of acompound of claim 1 or a prodrug thereof, to a patient in need thereof,wherein the autoimmune disease is selected from the group consisting ofsystemic lupus erythematosus, inflammatory bowel disease, diabetesmellitus, Sjögren's syndrome, scleroderma, and polymyositis, and whereinthe monogenic disorder is Aicardi-Goutiéres's Syndrome.
 17. A method forthe treatment of an autoimmune disease or a monogenic disorder, themethod comprising administering an effective amount of a compound ofFormula (III) or a prodrug thereof,

wherein R₁ is —H, halogen, —OH, —OCH₃, —NH₂, —NMe₂, —N(H)C(O)R₇ or —NO₂,wherein R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —CH₃,—CH₂CH₃, —CH₂ CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂CH₂CH₂CH₃, —CF₃, —CH₂CF₃ or

ring X is absent or

 wherein R₂ is —H, halogen, —NMe₂, —OCH₃ or —OCH₂CH₃; X is —H, —NH₂,

 wherein R₃ is —H or —CH₃; R₄ is —H or —CH₃; R₅ and R₆ are independently—H, —CH₃, —CH₂CH₃, —CH₂CH₂SH, —CH₂CH₂OH,

R_(Y) is —NO₂, —C(O)OCH₂CH₃ or —N(H)SO₂Me; and n is 2 or 3; to a patientin need thereof, wherein the autoimmune disease is selected from thegroup consisting of systemic lupus erythematosus, inflammatory boweldisease, diabetes mellitus, Sjögren's syndrome, scleroderma, andpolymyositis, and wherein the monogenic disorder is Aicardi-Goutiéres'sSyndrome.
 18. The method of claim 17, wherein the compound is of formula(IIIa):

wherein R₁ is —H, halogen, —OH, —OCH₃, —NH₂, —N(H)C(O)R₇ or —NO₂,wherein R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —CH₃,—CH₂CH₃, —CH₂ CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂CH₂CH₂CH₃, —CF₃, —CH₂CF₃ or

X is

 wherein R₃ is —H or —CH₃; R₄ is —H or —CH₃; R₅ and R₆ are independently—H, —CH₃, —CH₂CH₃ or —CH₂CH₂OH; and n is 2 or
 3. 19. The method of claim17, wherein the compound is of formula (IIIb):

wherein R₁ is —H, halogen, —OH, —OCH₃, —NH₂, —N(H)C(O)R₇ or —NO₂,wherein R₇ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH₂CH₂CH₂CH₃, —CH₃,—CH₂CH₃, —CH₂ CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂CH₂CH₂CH₂CH₃,—CH₂CH₂CH₂CH₂CH₂CH₃, —CF₃, —CH₂CF₃ or

R₂ is H, halogen, —OCH₃ or —OCH₂CH₃; X is —NH₂,

 wherein R₃ is —H or —CH₃; R₄ is —H or —CH₃; R₅ and R₆ are independently—H, —CH₃, —CH₂CH₃, —CH₂CH₂SH, —CH₂CH₂OH,

R_(Y) is —NO₂, —C(O)OCH₂CH₃ or —N(H)SO₂Me; and n is 2 or
 3. 20. Themethod of claim 16, for the treatment of systemic lupus erythematosus.21. The method of claim 16, for the treatment of Aicardi-Goutiéres'sSyndrome.